The long-range objectives of this research are the development and application of accurate experimental and rigorous theoretical methods of investigating the molecular detail and thermodynamic consequences of the interactions of cations with nucleic acids. These studies are of fundamental importance in polyelectrolyte chemistry, and have direct applications to the analysis of the interactions of nucleic acids with charged ligands of biological interest, including proteins and therapeutic agents. The stability and specificity of nucleic acid conformations and of complexes with charged ligands in aqueous solution are often determined by the electrolytes present and by competitive ion exchange processes involving cations on DNA. Thermodynamic measurements characterizing processes (conformational changes, ligand-binding) involving polymeric or oligomeric nucleic acids will be analyzed and interpreted by using Grand Canonical Monte Carlo (GCMC) simulations and calculations based on the Poisson-Boltzmann (PB) cell model. In these analyses, the fundamental thermodynamic variables are preferential interaction coefficients which reflect all nonideality due to interactions of electrolyte(s) with the specified state of the oligo- or polyelectrolyte component. Our GCMC and PB methods will be developed further in order to analyze equilibrium dialysis data on four component systems (water, nucleic acid, salt, oligocationic ligand). Current thermodynamic descriptions of salt effects on the extent of association of charged ligands with DNA will be examined at a fundamental level using these preferential interaction coefficients. The interactions of small cations with oligomeric and polymeric DNA will be studied quantitatively by NMR measurements on suitable quadrupolar nuclei in cations of biophysical interest. The dependences of the longitudinal and transverse relaxation rates of the probe nuclei (such as 23Na, 14N and 135Ba) on degree of polymerization, solution composition, temperature and (where appropriate) field strength, will be determined and analyzed to quantify the extent of association of individual cations with DNA, and the relative affinities of pairs of competing cations. These results will be compared with theoretical predictions for corresponding model systems calculated by canonical Monte Carlo (CBC) simulations or the PB cell model. Information about the dynamic character of the association of small ions with oligo- and polymeric nucleic acids will be obtained from determinations of quadrupolar NMR correlation times.